A short course of immunosuppressive therapy with Cyclosporin A (Cy-A) can induce immunological tolerance in rats to kidney and heart allografts. In contrast, continuous Cy-A treatment was needed to promote nerve allograft survival. Indeed, after stopping Cy-A, nerve rejection occurred and host axons that regenerated into the graft disappeared despite the fact that they are not foreign tissue and should not be the target of an immune response. Treatment of the graft rather than the recipient could be another way to induce tolerance. If the cell type(s) responsible for inciting the immune response could be removed from a nerve prior to its transplantation, tolerance to the nerve might develop. Intravascular blood cells and-or connective tissue cells could be the cause of nerve allograft rejection. Accordingly, the following treatments (alone or in combination) were used to remove these cells from 4-cm long ACI rat nerves prior to their transplantation into Fischer (FR) hosts: whole body perfusion with a physiological salt solution, whole body irradiation (1000 Rads from a cobalt source), systemic antilymphocyte serum therapy. After receiving the treatments cited, some nerves were desheathed of epineurium and perineurium and used as endoneurial allografts. Finally, ACI nerves, resident for 5 months in Cy-A-treated FR hosts, were retransplanted into new, untreated FR rats. This experiment addressed the question of whether a physiological turnover of endoneurial macrophages could alter nerve allograft immunogenicity. None of the treatments used induced tolerance to nerve allografts when they were examined 4 weeks postoperatively. All the allografts were infiltrated by mononuclear cells and Schwann, vascular and perineurial cells were absent. These results indicated that Schwann and-or vascular cells are immunogenic components of nerve. Because rat strains may differ in their response to short-term Cy-A therapy, we plan to examine the fate of nerve allografts in the original strain combinations (PVG and DA rats) where tolerance to kidney and heart allografts was described. Experiments will be performed to determine if host axonal loss can be prevented during nerve allograft rejection caused by the withdrawal of Cy-A. This might be possible since anti-inflammatory agents have been reported to decrease axonal loss caused by inflammation that develops after acute spinal cord injury. Reports that some host axons can regenerate through short lengths (2 cm) of rejected nerves prompted us to evaluate this method of nerve repair. In contrast to surviving nerve allografts, nerve segments formed after rejection had fewer axons, more neuromas, and no permeability barriers. These results should raise concern about using nerve allografts to repair nerves in nonimmunosuppressed recipients.